Synthesis of 5-substituted and 5,6-disubstituted furo[2,3-d]pyrimidines from 2-methylthio-4,6-pyrimidindione and bifunctional electrophiles

Article abstract of DOI:10.1016/j.tetlet.2019.03.017

A two-step protocol for the synthesis of 5-substituted or 5,6-disubstituted furo[2,3-d]pyrimidines using bifunctional electrophiles and a pyrimidine derivative was developed. The first step is O-alkylation of 2-methylthiopyrimidin-4,6-dione utilizing bifu

Full text of DOI:10.1016/j.tetlet.2019.03.017

Accepted Manuscript
Synthesis of 5-substituted and 5,6-disubstituted furo[2,3-d]pyrimidines from 2-
methylthio-4,6-pyrimidindione and bifunctional electrophiles
Gražina Petraitytė, Vytenis Vaitkevičius, Besra Özer, Viktoras Masevičius
PII:
S0040-4039(19)30225-4
https://doi.org/10.1016/j.tetlet.2019.03.017
TETL 50658
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 January 2019
5 March 2019
7 March 2019
Please cite this article as: Petraitytė, G., Vaitkevičius, V., Özer, B., Masevičius, V., Synthesis of 5-substituted and
5
,6-disubstituted furo[2,3-d]pyrimidines from 2-methylthio-4,6-pyrimidindione and bifunctional electrophiles,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.017
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Synthesis of 5-substituted and 5,6-disubstituted
furo[2,3-d]pyrimidines from 2-methylthio-4,6-
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pyrimidindione and bifunctional electrophiles
Gražina Petraitytė, Vytenis Vaitkevičius, Besra Özer, Viktoras Masevičius

1
Tetrahedron Letters
Synthesis of 5-substituted and 5,6-disubstituted furo[2,3-d]pyrimidines from 2-
methylthio-4,6-pyrimidindione and bifunctional electrophiles
a
a
a,b
a,
Gražina Petraitytė , Vytenis Vaitkevičius , Besra Özer , Viktoras Masevičius 
a
Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, 24 Naugarduko Street, Vilnius, Lithuania , LT.
Abant İzzet Baysal University, Bolu, Turkey.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A two-step protocol for the synthesis of 5-substituted or 5,6-disubstituted furo[2,3-d]pyrimidines
using bifunctional electrophiles and a pyrimidine derivative was developed. The first step is O-
alkylation of 2-methylthiopyrimidin-4,6-dione utilizing bifunctional electrophiles which are
readily available from the corresponding ketones via bromination or oxidative mesylation
procedures. The reaction furnishes 6-(2-oxoethoxy)pyrimidine derivatives in moderate yields,
and the di-O-alkylated product, while still unavoidable under the proposed conditions, is easily
removed upon recrystallization of the target compound. The second step is intramolecular
cyclization of the mono O-alkylated pyrimidines on silica gel to give the target furo[2,3-
d]pyrimidines in moderate to good yields.
Available online
Keywords:
O-alkylation
Bifunctional electrophile
Heterocycles
Pyrimidines
Cyclization
Furo[2,3-d]pyrimidines
2019 Elsevier Ltd. All rights reserved.
—
——

Corresponding author. Tel.: +370-5-233-0987; e-mail: viktoras.masevicius@chf.vu.lt

2
Tetrahedron Letters
1
. Introduction
either bromo or mesyl nucleofuge containing electrophiles gave
similar yields of target compound 4b using NaH, more varied
yields were obtained with other bases. A survey of the reaction
conditions was performed in the presence of potassium tert-
butoxide, triethylamine, DBU, DIPEA, sodium hydride and
potassium fluoride. While performing the reactions with all these
bases resulted in the formation of the target 2-methylthio-6-(2-
oxo-1,2-diphenylethoxy)pyrimidin-4-one 4a or 2-methylthio-6-
Designing/expanding methods for the formation of various
heterocyclic scaffolds is crucial for the advancement of medicinal
chemistry and materials sciences alike. Pyrimidine based
heterocycles are found amongst various biologically active
compounds as well as amongst compounds with promising
photophysical properties - furo[2,3-d]pyrimidine is one such
heterocycle. For the most part furo[2,3-d]pyrimidines have been
synthesized and investigated as potential inhibitors of folic acid
(
2-oxo-2-phenylethoxy)pyrimidin-4-one 4b, the best yields in
neat DMF were obtained when sodium hydride (32% for 4a and
5% for 4b) or potassium fluoride (38% for 4a and 14% for 4b)
1
1c
cycle enzymes, multireceptor tyrosine kinase inhibitors, and
1
2
glycogen synthase kinase-3 inhibitors. There are also indications
was applied. Due to the low solubility of the pyrimidinone salt
formed upon addition of sodium hydride or potassium fluoride in
DMF, water was added prior to addition of the alkylating agent.
This procedure gave mono O-alkylated products 4a and 4b in
that this heterocyclic motif can be employed to construct
oligoarylenes with potential applications in optoelectronic
3
devices.
6
2% and 63% yield, respectively. The main drawback of this
reaction is the formation of di-O-alkylated side-products
1529% isolated yield for compounds 5a-f). Due to the apparent
The construction of the furo[2,3-d]pyrimidine moiety can be
achieved via annulation of the pyrimidine or furan ring onto an
existing heterocycle. In the latter case, good candidates for
developing the furan ring are pyrimidines bearing an oxygen
(
difference in solubility of the mono O-alkylated products (4a-f)
and the undesired di-O-alkylated pyrimidines (5a-f) in benzene
and 1,2-dichloroethane, a simple recrystallization procedure was
utilised to separate these compounds. Additionally, no N-
alkylation products were 4aformed under these conditions.
Dolakova and co-workers
substituted-4,6-dihydroxypyrimidines afforded a mixture of N,O-
and di-O-alkylated products using chloro derivatives as
alkylating agents. In this case the authors also reported poor
solubility of the sodium salts of pyrimidinone in DMF which was
circumvented by using DMSO as a solvent. The reported
literature yields for the mono-O-alkylation of pyrimidin-2,4-
th
th
atom at the 4 or 6 position. There are several general strategies
for construction of the furo[2,3-d]pyrimidine skeleton involving
pyrimidinones. One is applying the Sonogashira coupling
reaction for the synthesis of 5-alkynylpyrimidinones and
subsequent annulation to form the target furo[2,3-
1
reported the alkylation of 2-
4
,5
d]pyrimidines. While this approach can be effectively applied
to the synthesis of various 6- and with an external electrophile
5
c
5
,6-disubstituted furo[2,3-d]pyrimidines, dialkynyl substrates
and alkynyl substrates bearing halogens are often outside of the
reaction scope for this protocol due to the competing bicoupling
6
and polycoupling of such alkynes, respectively. Also in some
1
4,15
dione reached up to 43%,
alkylated pyrimidinones 4a-f in moderate yields (4763%, see
Table 1).
while our procedure gave mono O-
cases Glaser-Elington homocoupling is a problem in the
7
4
Sonogashira reaction and in the annulation reaction as well.
Another approach to 5-arylfuro[2,3-d]pyrimidines proposed
8
by Dauzonne and Adam-Launay utilizes the reaction of
pyrimidin-4,6-dione with (Z)-(2-chloro-2-nitroethenyl)benzenes
as bifunctional electrophiles. While this protocol gives 5-
arylfuro[2,3-d]pyrimidines in moderate to good yields, it is
limited to 5-substituted furo[2,3-d]pyrimidines. Also the
bifunctional electrophiles used in this reaction are commercially
unavailable, but can be synthesized via a two-step protocol from
9
the corresponding benzaldehyde and nitromethane. A similar
strategy for synthesis of the furo[2,3-d]pyrimidine scaffold was
1
0
proposed by Li and Zhang using (E)-(2-nitroprop-1-en-1-
yl)arenes as bifunctional electrophiles. While the yields were
excellent (79-95%), this protocol was limited to furo[2,3-
th
d]pyrimidines with methyl or ethyl groups at the 6 position.
Other, more common, bifunctional electrophiles can be
utilized for the synthesis of 5-substituted furo[2,3-d]pyrimidines.
1
1
Earlier our group reported that selected 2,6-disubstituted
pyrimidin-4-ones readily react with ethyl bromopyruvate to
furnish furo[2,3-d]pyrimidine derivatives. Unfortunately, the
analogous reaction of 2-methylthiopyrimidin-4,6-dione with less
reactive -bromo carbonyl moiety possessing compounds did not
give the target furo[2,3-d]pyrimidines.
Scheme 1. Reagents and conditions: (i) (a) NaH or KF, DMF, 1 h, r.t.; (b)
H O, 2-substituted or 1,2-diphenyl-2-oxo methanesulfonate 2a-e, -10-0 °C to
2
2
r.t.; (ii) (a) NaH or KF, DMF, 1 h, r.t.; (b) H O, 1-substituted 2-bromo-1-
ethanone 3b-f, -10-0 °C to r.t.
The second step of the proposed protocol is an electrophilic
intramolecular cyclization reaction of 6-(2-oxoethoxy)pyrimidin-
2
. Results and Discussion
4
-one derivatives to the corresponding furo[2,3-d]pyrimidines.
We present herein a two-step protocol for the synthesis of 5-
The aryl- or tert-butyloxo group containing electrophiles are less
reactive (the latter is about 2 times less reactive than the former)
towards the pyrimidine 5 position in the intramolecular
electrophilic reaction compared to the previously reported
pyruvate moiety;
boiling point solvents (DMF, HMPA, diglyme, NMP,
nitrobenzene) with and without acidic catalysis (PTSA) were
substituted or 5,6-disubstituted furo[2,3-d]pyrimidines from 2-
methylthiopyrimidin-4,6-dione and bifunctional electrophiles
bearing an oxo group and a bromo or mesyl nucleofuge.
Bifunctional electrophiles can be readily prepared from the
th
1
2
11
corresponding methylketones by bromination or oxidative
thus harsh conditions were required. High
1
3
mesylation, while for benzoin only the latter option is viable.
While the O-alkylation of 2-methylthiopyrimidin-4,6-dione with

3
1
13
applied with no positive results, while adding ZnCl gave the
OCH2 H and C NMR shifts for compounds 4b-f are 5.7-5.2
2
target furopyrimidines in negligible amounts. Cyclization without
solvent upon melting gave the target furo[2,3-d]pyrimidines in
low yields (1525%) due to decomposition of the starting
material. When the reactions were carried out on silica gel at
elevated temperature (230240 °C) furo[2,3-d]pyrimidines 6a-f
were obtained in moderate to good (5076%) yields.
ppm and 68.4-66.6 ppm, respectively, while the same methylene
signals of the N-alkylation and C -alkylation products would be
5
found upfield. Subsequent intramolecular cyclization of
compounds 4a-f gives the target furo[2,3-d]pyrimidines 6a-f; this
was proven beyond doubt by X-ray crystallography of compound
1
8
6b (Fig. 1).
Figure 1. Crystal structure of compound 6b.
3
. Conclusion
In conclusion, an effective two-step protocol for the formation
of 5-substituted furo[2,3-d]pyrimidine derivatives has been
developed. The reactions proceed in moderate-to-good yields,
and silica gel appears to be a good choice for preventing
intermolecular interactions (thus the formation of side products
and decomposition) for high temperature intramolecular
reactions, when compared to the typical high boiling solvents or
performing the reaction upon compound melting.
Scheme 2. Reagents and conditions: (i) Silica gel, 230-240 °C (Wood’s
metal bath temperature).
The structural assignments of compounds 6a-f were based on
1
spectroscopic data. The H NMR spectra of compounds 4a-f
th
show a singlet peak for the proton at the pyrimidine 5 position
(
5.595.55 ppm). Conversely, furo[2,3-d]pyrimidines 6a-f lack
Acknowledgments
1
this singlet, and the H NMR spectra show a singlet peak for the
proton at the furo[2,3-d]pyrimidine 6 position (8.228.04 ppm).
Other H NMR spectroscopic data were also consistent with the
th
This work is a part of ongoing program “Synthesis and
functionalization of fused pyrimidine heterocycles, study on
heterocyclization reactions” (2015-2020). We would like to thank
Dr. Audrius Bucinskas for X-ray crystal structure measurements
and analysis.
1
expected structures.
Table 1. O-Alkylation yields for the reaction of 2-
methylthiopyrimidin-4,6-dione using NaH as a base and the
References and notes
yields of furo[2,3-d]pyrimidines.
1
Entry
R, R
Yield (%) Yield (%) Yield (%) Cyclization reaction
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4
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b
1
176; (b) Gangjee, A.; Zeng, Y.; McGuide, J. J.; Kisliuk, R. L. J.
1
2
3
4
5
Ph, Ph
Ph, H
4a (62) 5a (15)
6a (76)
6b (64)
6c (51)
6d (54)
6e (50)
6f (65)
70
55
Med. Chem. 2005, 48, 5329-5336; (c) Gangjee, A.; Li, W.; Lin,
L.; Zeng, Y.; Ihnat, M.; Warnke, L. A.; Green, D. W.; Cody, V.;
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4b (63) 5b (26)
4c (47) 5c (29)
4d (48) 5d (29)
4-Br-C
4-Ph-C
4-OMe-C
tert-butyl, H
6
H
4
, H
, H
60
45
6
H
4
(d) Gangjee, A.; Jain, H. D.; Phan, J.; Guo, X.; Queener, S. F.;
6
H
4
, H 4e (53) 5e (27)
4f (58) 5f (23)
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a
b
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L.; Smith, J. L.; Truesdale, A. T. Bioorg. Med. Chem. Lett. 2004,
isolated yields; methanesulfonate was used as a bifunctional electrophile.
1
4, 3907-3911; (b) Miyazaki, Y.; Meada, Y.; Sato, H.; Nakano,
M.; Mellor, G. W. Bioorg. Med. Chem. Lett. 2008, 18, 1967-
971.
1
3
Due to lactam-lactim tautomerism the C NMR spectra of O-
1
th
alkylated pyrimidines 4a-f lack peaks corresponding to the 4
3. (a) Hwang, E. J.; Cheong, C. S.; Lee, H.; Lee, S. W.; Lee, S. H.
Bull. Korean Chem. Soc. 2005, 26, 986-988; (b) Pyo, J. I.; Hwang,
E. J.; Cheong, C. S.; Lee, S. H.; Lee, S. W.; Kim, I. T.; Lee, S. H.
Synthetic Metals 2005, 155, 461-463.
th
and 6 pyrimidine carbons when recorded in DMSO-d6.
Recording the spectra in CDCl (4a and 4f) or Py-d (4b-e)
allowed all carbon peaks to be recorded, presumably due to a
change in tautomerism.
3
5
4
.
Janeba, Z.; Holý, A.; Pohl, R.; Snoeck, R.; Andrei, G.; De
Clercq, E.; Balzarini, J. Can. J. Chem. 2010, 88, 628-638.
5
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(a) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.;
Erichsen, J. T.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.
J. Med. Chem. 2000, 43, 4993-4997; (b) Blewett, S.; McGuigan,
C.; Baruki, H.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, I.
Nucleosides Nucleotides Nucleic Acid 2001, 20, 1063-1066; (c)
Liu, Z.; Li, D.; Li, S.; Bai, D.; He, X.; Hu, Y. Tetrahedron 2007,
This two-step synthetic protocol relies on selective O-
alkylation. N-Alkylation and C -alkylation pathways were also
5
6
3, 1931-1936.
6
7
8
.
.
.
Bunz, U. H. F. Chem. Rev. 2000, 100, 1605-1644.
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080.
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.
Dauzonne, D.; Demerseman, P. Synthesis 1990, 1, 66-70.
0. Li, C.; Zhang, F. Tetrahedron Lett. 2017, 58, 1572–1575.
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2. Rival, Y.; Taudou, A.; Ecalle, R. Farmaco 1993, 48, 857-869.
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007, 63, 4680-4687; (b) Cutulic, S. P. Y.; Findlay, N. J.; Zhou, S-
Z.; Chrystal, E. J. T.; Murphy, J. A. J. Org. Chem. 2009, 74, 8713-
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8
considered, but were excluded based on spectroscopic data. The
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Kašicka, V.; Holý, A. Eur. J. Med. Chem. 2009, 44, 2408-2424;

4
Tetrahedron Letters
(
b) Břehová, P.; Česnek, M.; Dračínský, M.; Holý, A.; Janeba, Z.
alkylated pyrimidone (1.1 mmol), silica gel (10 times the starting
material in grams) and CHCl (25 mL) was stirred for 0.5 h at
Tetrahedron 2011, 67, 7379-7385.
3
1
1
5. Liu, Y.; Zhang, Q.; Chen, L.-H.; Yang, H.; Lu, W.; Xie, X.; Nan,
F.-J. ACS Med. Chem. Lett. 2016, 7, 579-583.
6. General procedure for the synthesis of 2-methylthiopyrimidin-
room temperature. After solvent evaporation under reduced
pressure, the flask with silica gel and starting material was placed
in a Wood’s metal bath preheated to 230-240 °C. The silica gel
inside the flask was stirred until completion of cyclization reaction
(approximately 1 h, TLC monitoring). The target product was
isolated by eluting the reaction content through a layer of fresh
silica gel (1-2 cm) using CHCl -EtOAc (9:1). The solvents were
3
evaporated under reduced pressure and the residue recrystallized
to afford the target furo[2,3-d]pyrimidines.
4
(
(3H)-ones 4. To a solution of 2-methylthiopyrimidin-4,6-dione
0.17 g, 1.07 mmol) in DMF (4 mL) sodium hydride 60%
dispersion in oil (38 mg, 1.6 mmol) or potassium fluoride (57 mg,
.97 mmol) was added and the mixture stirred for 1 h at room
temperature. Then, H O (approximately 1.5 mL) was added to the
0
2
reaction mixture until the pyrimidone salt completely dissolved.
The reaction mixture was cooled to -10 °C and the corresponding
methanesulfonate or 2-bromo-1-arylethanone (0.97 mmol) was
added. The reaction mixture was left to reach r.t. and stirred for
approximately 48 h (TLC monitoring of the alkylating agent).
Water was added to the reaction mixture and the formed
precipitate was filtered off, washed with water and recrystallized
to give the target compound.
18. X-ray data (CCDC No. 1900559) can be obtained free of charge
from the Cambridge Crystallographic Data Center.
1
7. General procedure for the synthesis of 2-methylthiofuro[2,3-
d]pyrimidin-4(3H)-ones 6. A mixture of the corresponding O-
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5
Highlights:
-substituted furo[2,3-d]pyrimidines from pyrimidines and
5
bifunctional electrophiles
Silica gel is a “solvent” of choice for intramolecular reactions
at high temperature
Lactam-lactim tautomerism can be source of unaccounted
1
3
carbons in C NMR spectra